Jean-Pierre Girolami - Academia.edu (original) (raw)
Papers by Jean-Pierre Girolami
Journal of Cardiovascular Pharmacology, 1992
We investigated the effect of two oral (p.o.) doses of cicletanine (5 and 30 mg/kg/day) for 4 wee... more We investigated the effect of two oral (p.o.) doses of cicletanine (5 and 30 mg/kg/day) for 4 weeks on urinary excretion (UKE), renal concentration (RKC) of kallikrein, and prostaglandin E2 (PGE2) and 6-keto-PGF1 alpha urinary excretion of stroke-prone (SP) spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) rats submitted to a high sodium intake (1%). Both doses of cicletanine induced a significant antihypertensive effect in treated SHR as compared with hypertensive untreated controls (HC). After 4-week treatment, a significant difference in mortality was observed between normotensive controls (NC) (0%) and HC (84%). Both doses of cicletanine reduced the mortality of hypertensive animals (8% SHR with 5 mg and 24% SHR with 30 mg vs. 84% in HC). Whereas UKE and RKC were decreased in HC during the progression of untreated hypertension from week 1 to week 4, both doses of cicletanine administration significantly prevented this decrease. Consistently with maintenance of UKE during the course of hypertension, the level of tissue kallikrein was higher in hypertensive cicletanine-treated than in untreated SHR. This increased RKC was associated with a significantly higher rate of kallikrein biosynthesis. The increased level of the urinary excretion and tissue concentration of PGE2 and 6-keto-PGF1 alpha in cicletanine-treated SHR as compared with untreated animals was also of interest. This protective effect on PG excretion correlated with that on kallikrein excretion. The results confirm the efficiency of cicletatine as an antihypertensive treatment. The antihypertensive action includes protective effects on potential vasodepressor kallikrein-kinin and prostaglandin systems.(ABSTRACT TRUNCATED AT 250 WORDS)
Biochemical and Biophysical Research Communications, 2005
Recently, we have described a novel protein-protein interaction between the G-protein coupled bra... more Recently, we have described a novel protein-protein interaction between the G-protein coupled bradykinin B2 receptor and tyrosine phosphatase SHP-2 via an immunoreceptor tyrosine-based inhibition motif (ITIM) sequence located in the C-terminal part of the B2 receptor and the Src homology (SH2) domains of SHP-2. Here we show that phospholipase C (PLC)c1, another SH2 domain containing protein, can also interact with this ITIM sequence. Using surface plasmon resonance analysis, we observed that PLCc1 interacted with a peptide containing the phosphorylated form of the bradykinin B2 receptor ITIM sequence. In CHO cells expressing the wild-type B2 receptor, bradykinin-induced transient recruitment and activation of PLCc1. Interestingly, this interaction was only observed in quiescent and not in proliferating cells. Mutation of the key ITIM residue abolished this interaction with and activation of PLCc1. Finally we also identified bradykinin-induced PLCc1 recruitment and activation in primary culture renal mesangial cells.
Journal of Clinical Investigation, 2002
Kidney International, 1999
Serotonin metabolism in rat mesangial cells: Involvement of a role in the regulation of glomerula... more Serotonin metabolism in rat mesangial cells: Involvement of a role in the regulation of glomerular filtration rate [1] serotonin transporter and monoamine oxidase A. and participate in the development of functional and Background. Serotonin is one of the factors regulating mesmorphological glomerular abnormalities in inflammaangial cell proliferation, and convergent evidence supports its tory processes [2]. The function of MCs is regulated involvement in the development of glomerulonephritis. In this by a variety of mediators, including biogenic amines, study, we identified a serotonin transporter and the aminedegrading enzyme monoamine oxidases (MAOs) in mesangial angiotensin II, bradykinin, growth factors, and cytokines cells, and we studied their involvement in serotonin degradagenes sharing a common intron/exon organization [18], have been identified based on substrate specificity:
Journal of Hypertension, 1987
Different sodium intakes may affect or alter the urinary excretion of renal kallikrein. We have c... more Different sodium intakes may affect or alter the urinary excretion of renal kallikrein. We have compared the renal and the urinary effects of sodium depletion and sodium loading with 1% NaCl on total kallikrein, using a direct radio-immunoassay against immunoreactive kallikrein and on active kallikrein assessed by a kininogenase assay with a kinin radio-immunoassay. Sodium depletion resulted in an increase in renal and urinary excretion of both the immunoreactive kallikrein and the kininogenase activity. Sodium loading resulted in a slight but significant decrease in renal tissue immunoreactive kallikrein content without any change in the kininogenase activity, while the urinary excretion of the kininogenase activity was greatly increased and the urinary immunoreactive kallikrein remained steady. This sodium depletion induces consistent effects at the renal and urinary level, resulting probably from a stimulation of biosynthesis. However, during sodium loading, renal and urinary measurements of kallikrein are dissociated. Furthermore, kininogenase activity and immunoreactive kallikrein are not correlated in either of the two studied compartments. Thus sodium loading seems to induce independent effects at the renal and urinary levels, possibly resulting from different mechanisms.
Synapse, 2005
A role for kinin B1 receptors was suggested in the spinal cord and peripheral organs of streptozo... more A role for kinin B1 receptors was suggested in the spinal cord and peripheral organs of streptozotocin (STZ)-diabetic rats. The present study aims at determining whether B1 receptors are also induced and over-expressed in the brain of STZ-rats at 2, 7, and 21 days post-treatment. This was addressed by in situ hybridization using the [35S]-UTPαS-labeled riboprobe and by in vitro autoradiography with the radioligand [125I]-HPP-des-Arg10-Hoe 140. In control rats, B1 receptor mRNA was found widely distributed in many brain regions. Low mRNA levels were found in thalamus and hypothalamus (7–12 nCi/g) while high mRNA signals were detected in cortical regions and hippocampus (18–29 nCi/g). In diabetic rats, B1 receptor mRNA was markedly increased in hippocampus, temporal/parietal cortices and amygdala at 2 and 7 days (+88 to +150%). Low densities of B1 receptor binding sites were detected in all analyzed regions in control rats (0.18–0.37 fmol/mg tissue). In diabetic rats, B1 receptor binding sites were significantly increased in hippocampus, amygdala, temporal/parietal, and perhinal/piriform cortices (+ 55 to + 165 %) at 7 days only. Results highlight an early but transient and reversible up-regulation of B1 receptors in specific brain regions of STZ-diabetic rats. This may offer the advantage of reducing putative central side effects with B1 receptor antagonists if used for the treatment of diabetic complications in the periphery. Synapse 57:29–37, 2005. © 2005 Wiley-Liss, Inc.
Nephron, 1993
In the present study, we investigated the plasma, urinary and intrarenal concentrations of low an... more In the present study, we investigated the plasma, urinary and intrarenal concentrations of low and high molecular weight kininogens during sodium chromate (25 mg/kg body weight)-induced acute renal failure (ARF) in the rat. Urinary kininogen underwent a transient increase with a maximum on day 7 (78 +/- 22 versus 4.2 +/- 1.6 ng bradykinin/mg creatinine) whereas plasma kininogen did not and glomerular filtration rate decreased (92 +/- 8 versus 895 +/- 70 microliters/min). The tissue level of kininogen was enhanced both in the cortex (1,319 +/- 123 versus 86 +/- 8 pg bradykinin Eq/mg protein) and in the medulla (1,673 +/- 138 versus 44 +/- 9 pg bradykinin Eq/mg protein) but more in the medulla (36 +/- 4- versus 15 +/- 3-fold). As plasma kininogen level was unchanged and glomerular filtration rate decreased, the increase in both renal concentration and urinary excretion of kininogen probably reflects stimulated renal production of kininogen in this model of ARF. Whether the evoked renal production of kininogen results from a local inflammatory response only or may subserve another physiological purpose remains to be elucidated.
British Journal of Pharmacology, 1997
A transient two fold increase in the cyclic GMP content was observed in rat freshly isolated glom... more A transient two fold increase in the cyclic GMP content was observed in rat freshly isolated glomeruli 6 to 9 h after a single subcutaneous injection of 20 mg kg−1 cyclosporine A (CsA) in conscious animals.In vitro stimulation with endothelin 3 (ET-3) of isolated glomeruli obtained from CsA-untreated rats resulted in a dose-dependent increase in cyclic GMP content. The increase observed with 10 nM ET-3 was similar to that observed in glomeruli isolated 9 h after in vivo CsA administration.The rise in glomerular cyclic GMP content after in vivo CsA injection was prevented by in vivo treatment with L-NAME (10 mg kg−1) or by in vitro calcium deprivation of the incubation medium.The stimulating effects of CsA on glomerular cyclic GMP content were inhibited by in vivo administration of the ETB receptor antagonist BQ-788 (2 mg kg−1) but not by the ETA receptor antagonist BQ-123 (2 mg kg−1).The maximum increase in glomerular cyclic GMP content induced in vitro by acetylcholine (100 μM) and by ET-3 (100 nM) was slightly lower (approximately by 20–25%, P<0.05) in glomeruli from CsA-treated rats than in glomeruli from untreated rats. In contrast, the maximum increase achieved with 1 μM sodium nitroprusside was similar in both groups.A single subcutaneous injection of CsA did not significantly alter the glomerular mRNA expression of constitutive endothelial NO synthase (eNOS), as evaluated by RT–PCR, whereas the mRNA expression of the inducible NO synthase (iNOS), which follows pretreatment with lipopolysaccharide, was prevented.These results indicate that in vivo administration of a single dose of cyclosporine A transiently increases the cyclic GMP content of freshly isolated glomeruli, and that activation of ETB receptors and stimulation of the NO pathway are involved in this process. Furthermore, a single administration of CsA does not impair eNOS mRNA expression and only slightly reduces NO-dependent glomerular cyclic GMP production.A transient two fold increase in the cyclic GMP content was observed in rat freshly isolated glomeruli 6 to 9 h after a single subcutaneous injection of 20 mg kg−1 cyclosporine A (CsA) in conscious animals.In vitro stimulation with endothelin 3 (ET-3) of isolated glomeruli obtained from CsA-untreated rats resulted in a dose-dependent increase in cyclic GMP content. The increase observed with 10 nM ET-3 was similar to that observed in glomeruli isolated 9 h after in vivo CsA administration.The rise in glomerular cyclic GMP content after in vivo CsA injection was prevented by in vivo treatment with L-NAME (10 mg kg−1) or by in vitro calcium deprivation of the incubation medium.The stimulating effects of CsA on glomerular cyclic GMP content were inhibited by in vivo administration of the ETB receptor antagonist BQ-788 (2 mg kg−1) but not by the ETA receptor antagonist BQ-123 (2 mg kg−1).The maximum increase in glomerular cyclic GMP content induced in vitro by acetylcholine (100 μM) and by ET-3 (100 nM) was slightly lower (approximately by 20–25%, P<0.05) in glomeruli from CsA-treated rats than in glomeruli from untreated rats. In contrast, the maximum increase achieved with 1 μM sodium nitroprusside was similar in both groups.A single subcutaneous injection of CsA did not significantly alter the glomerular mRNA expression of constitutive endothelial NO synthase (eNOS), as evaluated by RT–PCR, whereas the mRNA expression of the inducible NO synthase (iNOS), which follows pretreatment with lipopolysaccharide, was prevented.These results indicate that in vivo administration of a single dose of cyclosporine A transiently increases the cyclic GMP content of freshly isolated glomeruli, and that activation of ETB receptors and stimulation of the NO pathway are involved in this process. Furthermore, a single administration of CsA does not impair eNOS mRNA expression and only slightly reduces NO-dependent glomerular cyclic GMP production.
Canadian Journal of Physiology and Pharmacology, 2002
We investigated the effects of a 3-week treatment with various combinations of angiotensin-conver... more We investigated the effects of a 3-week treatment with various combinations of angiotensin-converting enzyme inhibitor (ACEI) and B 1 and B 2 bradykinin receptor (B 1 R and B 2 R) antagonists (B 1 A and B 2 A) and AT1 receptor antagonist on ERK 1 and 2 phosphorylation in isolated glomeruli from streptozotocin-treated diabetic rats (STZ rats). Body weight, glycemia, and blood pressure were monitored. The rats were divided into nine groups: (1) control; and groups 2-9 were STZ treated with (3) insulin, (4) ACEI, (5) ACEI + B 1 A, (6) ACEI + B 2 A, (7) B 2 A, (8) B 1 A, (9) AT1 antagonist. ERK 1 and 2 phosphorylation and expression of B 1 R and B 2 R were assessed by Western blot analysis. ERK 1 and 2 phosphorylation was higher in STZ rats; this activation was normalized by insulin and reduced by ACEI but not by AT1 antagonist. The reduction of ERK 1 and 2 phosphorylation by the ACEI was reversed by B 1 A and B 2 A. The induction of B 1 R was confirmed by increased expression of mRNA and B 1 receptor protein. Since ERK 1 and 2 phosphorylation is an early event in the induction of matrix secretion and hyperproliferation associated with diabetic nephropathy, activation of B 1 R and B 2 R appears to be a useful pharmacological target in the management of this pathology.
Anesthesiology, 2008
The aim of this study was to validate a model of postfracture pain in mice, which was evaluated i... more The aim of this study was to validate a model of postfracture pain in mice, which was evaluated in the presence and the absence of morphine and ketoprofen. The study was divided into two parts: protocol A, the effects of closed fracture; and protocol B, the effects of morphine and ketoprofen on fracture pain. In protocol A, mice were assigned to three groups: group 1, sham incision; group 2, sham pinning; or group 3, fracture. In protocol B, mice were randomly assigned to four groups to receive morphine (3 or 10 mg/kg body weight), ketoprofen (50 mg/kg body weight), or placebo (vehicle). Three tests were used to assess pain behavior: von Frey filament application, hot plate test, and a subjective pain scale. In protocol A, thermal nociception, mechanical nociception, and subjective pain were significantly modified in group 3 (fractured) compared with control groups 1 and 2 (sham groups). In protocol B, when tests were repeated for 240 min in morphine-treated animals and in ketoprofen-treated animals, reduction of mechanical nociception, thermal nociception, and subjective pain scale score were observed. Morphine and ketoprofen administration provided the same effect on behavioral testing on postoperative days 1 and 2. This mouse model seems to be a reliable and reproducible tool to investigate the effect of closed bone fracture on several parameters, such as pain, remodeling, and recovery. Moreover, it allows studying the effects of various pharmacologic treatments as well as the involvement of various systems using different genetically modified strains of mice.
Kidney International, 2002
leading to diabetic nephropathy. Insulin-like growth facgenesis in mesangial cells by bradykinin.... more leading to diabetic nephropathy. Insulin-like growth facgenesis in mesangial cells by bradykinin. tor-I (IGF-I) and to a lesser extent insulin, both induce Background. The beneficial effects of therapeutic angioten-MC proliferation and collagen secretion most likely via sin-converting enzyme (ACE) inhibitor treatment against the
European Journal of Pharmacology, 1995
This study examined the effect of various manipulations of intracellular Ca2+ on kallikrein relea... more This study examined the effect of various manipulations of intracellular Ca2+ on kallikrein release by renal cortical slices. Increasing the extracellular Ca2+ concentration and the addition of Ca2+ ionophore A23187 was without effect on kallikrein release. In contrast, kallikrein release was enhanced by the addition of either extracellular or intracellular Ca2+ chelators in Ca(2+)-free medium and by two Ca2+ channel blockers, verapamil and nifedipine. Kallikrein release was also highly enhanced in depolarising medium (10-100 mM potassium chloride). Since potassium chloride induced a dose-related increase in free cytosolic Ca2+ which was abolished by nifedipine whereas the stimulation of kallikrein secretion persisted, a direct stimulating effect of potassium, at least at sub-physiological concentration, is suggested. Similarily, inhibition of either sodium/potassium-ATPase and Ca2+ ATPase by ouabain and vanadium respectively, was also without effect on kallikrein secretion. Taken together, these results indicate that intracellular Ca2+ depletion, Ca2+ channel blockers and high extracellular K+ concentrations, acting through different mechanisms, are effective stimuli for kallikrein secretion, at least in the isolated renal cortical slice.
Kidney International, 1998
Background. Under physiological conditions, the effects of kinins in the kidney are mainly mediat... more Background. Under physiological conditions, the effects of kinins in the kidney are mainly mediated by the bradykinin B2-receptor, whereas the kinin B1-receptor is strongly induced under inflammatory conditions in a variety of tissues. Knowledge of the distribution of the B1-receptor along the nephron is of importance since the B1-receptor might replace B2-receptors under these conditions.
European Journal of Pharmacology, 1995
We investigated the effects of bradykinin on glomerular bradykinin B2 receptor functions and para... more We investigated the effects of bradykinin on glomerular bradykinin B2 receptor functions and parameters in vivo, after intrarenal infusion of bradykinin, and in vitro, after incubation of isolated rat glomeruli with bradykinin. Bradykinin transiently increased renal plasma flow whereas a second challenge was ineffective. Scatchard analysis demonstrated the presence of two populations of bradykinin binding sites whose densities were similarly decreased by about 40% after intrarenal bradykinin infusion. This decrease was not altered by an acid wash suggesting internalization of the radiolabelled ligand. The effect of bradykinin was prevented by a bradykinin B2 receptor antagonist. Pre-exposure of isolated rat glomeruli to bradykinin mimicked the in vivo results because there was a reduction in bradykinin-induced prostaglandin E2 and prostaglandin F2 alpha release. Rapid recovery was observed 15 min after washing out the bradykinin. Our results directly demonstrate a negative homologous down-regulation of B2 glomerular bradykinin receptor density under both in vivo and in vitro conditions, an effect which involves a rapid sequestration of the receptor.
Background-The physiological effects of ACE inhibitors may act in part through a kinin-dependent ... more Background-The physiological effects of ACE inhibitors may act in part through a kinin-dependent mechanism. We investigated the effect of chronic ACE-inhibitor treatment on functional kinin B 1 -and B 2 -receptor expression, which are the molecular entities responsible for the biological effects of kinins. Methods and Results-Rats were subjected to different 6-week treatments using various mixtures of the following agents: ACE inhibitor, angiotensin AT 1 -receptor antagonist, and B 1 -and B 2 -receptor antagonists. Chronic ACE inhibition induced both renal and vascular B 1 -receptor expression, whereas B 2 -receptor expression was not modified. Furthermore, with B 1 -receptor antagonists, it was shown that B 1 -receptor induction was involved in the hypotensive effect of ACE inhibition. Using microdissection, we prepared 10 different nephron segments and found ACE-inhibitor-induced expression of functional B 1 -receptors in all segments. ACE-inhibitor-induced B 1 -receptor induction involved homologous upregulation, because it was prevented by B 1 -receptor antagonist treatment. Finally, using B 2 -receptor knockout mice, we showed that ACE-inhibitor-induced B 1 -receptor expression was B 2 -receptor independent. Conclusions-This study provides the first evidence that chronic ACE-inhibitor administration is associated with functional vascular and renal B 1 -receptor induction, which is involved in ACE-inhibitor-induced hypotension. The observed B 1 -receptor induction in the kidney might participate in the known renoprotective effects of ACE inhibition.
In addition to being a pro-inflammatory mediator, bradykinin is now recognized as a neuromediator... more In addition to being a pro-inflammatory mediator, bradykinin is now recognized as a neuromediator and regulator of several vascular and renal functions. New breakthroughs point to unusual and atypical signalling pathways for a G-protein coupled receptor that could explain the anti-proliferative and anti-fibrogenic effects of bradykinin. The availability of transgenic and knock out animal models for bradykinin receptors or bradykinin-synthesizing or -catabolic enzymes confirms these cardiac and renal protective roles for this peptide system. Bradykinin receptors are involved in the therapeutic action of angiotensin-1 converting enzyme inhibitors that are used in the treatment of arterial hypertension, heart failure and diabetes. Nevertheless, recent evidence highlights dissimilar mechanisms in the regulation and function of these receptors between the central nervous system and peripheral tissues. Therefore, the development of more specific bradykinin receptor agonists or antagonists devoid of central actions seems to evolve as a new therapeutic approach.
Angiotensin II regulates vascular structure through growth and apoptosis, with implications in pa... more Angiotensin II regulates vascular structure through growth and apoptosis, with implications in pathophysiology. Subtypes of vascular smooth muscle cells with specific morphology, growth, or apoptotic features have been isolated. Here, we investigated the effects of angiotensin II on apoptosis of 2 morphologically different rat aortic smooth muscle cell phenotypes. Spindle and epithelioid cell lines cultured under low serum conditions were stimulated by angiotensin II. Responsiveness was evaluated by calcium signaling. In both phenotypes, an angiotensin II type 1 receptor-mediated transient intracellular calcium peak arose from intracellular pools. However, a sustained nifedipine-sensitive calcium entry occurred specifically in epithelioid cells. Angiotensin II did not impair spindle cell survival, whereas a delayed reduction in cell number occurred in epithelioid cells. Cell death through apoptosis was characterized by cellular and nuclear morphology. Consistently, DNA fragmentation, evaluated by biochemical quantification, nuclei staining, and ladders, and caspase 3-like activity were promoted by angiotensin II in epithelioid cells. Kinetics of annexin V binding showed that apoptosis was a delayed process. Angiotensin II-induced apoptosis of epithelioid cells was prevented by angiotensin II type 1 but not type 2 receptor antagonists and was inhibited by a calcium chelator or calcium antagonist. Conversely, epithelioid cell apoptosis could be induced by a calcium ionophore. Thus, the death signaling promoted by angiotensin II in epithelioid cells involves type 1 receptor-mediated calcium entry. These data suggest that angiotensin II can promote angiotensin II type 1 receptor-mediated apoptosis in vascular smooth muscle cells, depending on their phenotype. This process may play a role in vascular remodeling in cardiovascular diseases. (Hypertension. 2001;38: 1294-1299.)
Canadian Journal of Physiology and Pharmacology, 2002
Several experimental data document an activation of the mitogen-activated protein kinases Erk1 an... more Several experimental data document an activation of the mitogen-activated protein kinases Erk1 and Erk2 by bradykinin (BK), an agonist of the kinin B2 receptor (B2R). In contrast, other reports showed an inhibitory modulation of mitogenesis by BK. Therefore, we explored in the isolated glomeruli the effect of B2R activation on the signaling of insulin-like growth factor-1 (IGF-1), platelet-derived growth factor-BB (PDGF-BB), and high glucose (HG), three factors that are believed to be involved in the development of glomerulosclerosis via the phosphorylation of Erk1 and Erk2. We observed that the activation of B2R negatively modulates the phosphorylation of Erk1 and Erk2 induced by IGF-1, PDGF-BB, and HG in the glomerulus. These effects are consistent with the hypothesis of a protective role for BK in the kidney during development of glomerulosclerosis and renal pathologies associated with a hyperproliferative state.
Bradykinin B2 receptor knockout mice (B 2 -/-) have been useful to study the role of bradykinin u... more Bradykinin B2 receptor knockout mice (B 2 -/-) have been useful to study the role of bradykinin under pathological conditions. Using these mice it was shown that bradykinin plays an important role in angiogenesis, heart failure, salt induced hypertension and kidney fibrosis.
Journal of Cardiovascular Pharmacology, 1992
We investigated the effect of two oral (p.o.) doses of cicletanine (5 and 30 mg/kg/day) for 4 wee... more We investigated the effect of two oral (p.o.) doses of cicletanine (5 and 30 mg/kg/day) for 4 weeks on urinary excretion (UKE), renal concentration (RKC) of kallikrein, and prostaglandin E2 (PGE2) and 6-keto-PGF1 alpha urinary excretion of stroke-prone (SP) spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) rats submitted to a high sodium intake (1%). Both doses of cicletanine induced a significant antihypertensive effect in treated SHR as compared with hypertensive untreated controls (HC). After 4-week treatment, a significant difference in mortality was observed between normotensive controls (NC) (0%) and HC (84%). Both doses of cicletanine reduced the mortality of hypertensive animals (8% SHR with 5 mg and 24% SHR with 30 mg vs. 84% in HC). Whereas UKE and RKC were decreased in HC during the progression of untreated hypertension from week 1 to week 4, both doses of cicletanine administration significantly prevented this decrease. Consistently with maintenance of UKE during the course of hypertension, the level of tissue kallikrein was higher in hypertensive cicletanine-treated than in untreated SHR. This increased RKC was associated with a significantly higher rate of kallikrein biosynthesis. The increased level of the urinary excretion and tissue concentration of PGE2 and 6-keto-PGF1 alpha in cicletanine-treated SHR as compared with untreated animals was also of interest. This protective effect on PG excretion correlated with that on kallikrein excretion. The results confirm the efficiency of cicletatine as an antihypertensive treatment. The antihypertensive action includes protective effects on potential vasodepressor kallikrein-kinin and prostaglandin systems.(ABSTRACT TRUNCATED AT 250 WORDS)
Biochemical and Biophysical Research Communications, 2005
Recently, we have described a novel protein-protein interaction between the G-protein coupled bra... more Recently, we have described a novel protein-protein interaction between the G-protein coupled bradykinin B2 receptor and tyrosine phosphatase SHP-2 via an immunoreceptor tyrosine-based inhibition motif (ITIM) sequence located in the C-terminal part of the B2 receptor and the Src homology (SH2) domains of SHP-2. Here we show that phospholipase C (PLC)c1, another SH2 domain containing protein, can also interact with this ITIM sequence. Using surface plasmon resonance analysis, we observed that PLCc1 interacted with a peptide containing the phosphorylated form of the bradykinin B2 receptor ITIM sequence. In CHO cells expressing the wild-type B2 receptor, bradykinin-induced transient recruitment and activation of PLCc1. Interestingly, this interaction was only observed in quiescent and not in proliferating cells. Mutation of the key ITIM residue abolished this interaction with and activation of PLCc1. Finally we also identified bradykinin-induced PLCc1 recruitment and activation in primary culture renal mesangial cells.
Journal of Clinical Investigation, 2002
Kidney International, 1999
Serotonin metabolism in rat mesangial cells: Involvement of a role in the regulation of glomerula... more Serotonin metabolism in rat mesangial cells: Involvement of a role in the regulation of glomerular filtration rate [1] serotonin transporter and monoamine oxidase A. and participate in the development of functional and Background. Serotonin is one of the factors regulating mesmorphological glomerular abnormalities in inflammaangial cell proliferation, and convergent evidence supports its tory processes [2]. The function of MCs is regulated involvement in the development of glomerulonephritis. In this by a variety of mediators, including biogenic amines, study, we identified a serotonin transporter and the aminedegrading enzyme monoamine oxidases (MAOs) in mesangial angiotensin II, bradykinin, growth factors, and cytokines cells, and we studied their involvement in serotonin degradagenes sharing a common intron/exon organization [18], have been identified based on substrate specificity:
Journal of Hypertension, 1987
Different sodium intakes may affect or alter the urinary excretion of renal kallikrein. We have c... more Different sodium intakes may affect or alter the urinary excretion of renal kallikrein. We have compared the renal and the urinary effects of sodium depletion and sodium loading with 1% NaCl on total kallikrein, using a direct radio-immunoassay against immunoreactive kallikrein and on active kallikrein assessed by a kininogenase assay with a kinin radio-immunoassay. Sodium depletion resulted in an increase in renal and urinary excretion of both the immunoreactive kallikrein and the kininogenase activity. Sodium loading resulted in a slight but significant decrease in renal tissue immunoreactive kallikrein content without any change in the kininogenase activity, while the urinary excretion of the kininogenase activity was greatly increased and the urinary immunoreactive kallikrein remained steady. This sodium depletion induces consistent effects at the renal and urinary level, resulting probably from a stimulation of biosynthesis. However, during sodium loading, renal and urinary measurements of kallikrein are dissociated. Furthermore, kininogenase activity and immunoreactive kallikrein are not correlated in either of the two studied compartments. Thus sodium loading seems to induce independent effects at the renal and urinary levels, possibly resulting from different mechanisms.
Synapse, 2005
A role for kinin B1 receptors was suggested in the spinal cord and peripheral organs of streptozo... more A role for kinin B1 receptors was suggested in the spinal cord and peripheral organs of streptozotocin (STZ)-diabetic rats. The present study aims at determining whether B1 receptors are also induced and over-expressed in the brain of STZ-rats at 2, 7, and 21 days post-treatment. This was addressed by in situ hybridization using the [35S]-UTPαS-labeled riboprobe and by in vitro autoradiography with the radioligand [125I]-HPP-des-Arg10-Hoe 140. In control rats, B1 receptor mRNA was found widely distributed in many brain regions. Low mRNA levels were found in thalamus and hypothalamus (7–12 nCi/g) while high mRNA signals were detected in cortical regions and hippocampus (18–29 nCi/g). In diabetic rats, B1 receptor mRNA was markedly increased in hippocampus, temporal/parietal cortices and amygdala at 2 and 7 days (+88 to +150%). Low densities of B1 receptor binding sites were detected in all analyzed regions in control rats (0.18–0.37 fmol/mg tissue). In diabetic rats, B1 receptor binding sites were significantly increased in hippocampus, amygdala, temporal/parietal, and perhinal/piriform cortices (+ 55 to + 165 %) at 7 days only. Results highlight an early but transient and reversible up-regulation of B1 receptors in specific brain regions of STZ-diabetic rats. This may offer the advantage of reducing putative central side effects with B1 receptor antagonists if used for the treatment of diabetic complications in the periphery. Synapse 57:29–37, 2005. © 2005 Wiley-Liss, Inc.
Nephron, 1993
In the present study, we investigated the plasma, urinary and intrarenal concentrations of low an... more In the present study, we investigated the plasma, urinary and intrarenal concentrations of low and high molecular weight kininogens during sodium chromate (25 mg/kg body weight)-induced acute renal failure (ARF) in the rat. Urinary kininogen underwent a transient increase with a maximum on day 7 (78 +/- 22 versus 4.2 +/- 1.6 ng bradykinin/mg creatinine) whereas plasma kininogen did not and glomerular filtration rate decreased (92 +/- 8 versus 895 +/- 70 microliters/min). The tissue level of kininogen was enhanced both in the cortex (1,319 +/- 123 versus 86 +/- 8 pg bradykinin Eq/mg protein) and in the medulla (1,673 +/- 138 versus 44 +/- 9 pg bradykinin Eq/mg protein) but more in the medulla (36 +/- 4- versus 15 +/- 3-fold). As plasma kininogen level was unchanged and glomerular filtration rate decreased, the increase in both renal concentration and urinary excretion of kininogen probably reflects stimulated renal production of kininogen in this model of ARF. Whether the evoked renal production of kininogen results from a local inflammatory response only or may subserve another physiological purpose remains to be elucidated.
British Journal of Pharmacology, 1997
A transient two fold increase in the cyclic GMP content was observed in rat freshly isolated glom... more A transient two fold increase in the cyclic GMP content was observed in rat freshly isolated glomeruli 6 to 9 h after a single subcutaneous injection of 20 mg kg−1 cyclosporine A (CsA) in conscious animals.In vitro stimulation with endothelin 3 (ET-3) of isolated glomeruli obtained from CsA-untreated rats resulted in a dose-dependent increase in cyclic GMP content. The increase observed with 10 nM ET-3 was similar to that observed in glomeruli isolated 9 h after in vivo CsA administration.The rise in glomerular cyclic GMP content after in vivo CsA injection was prevented by in vivo treatment with L-NAME (10 mg kg−1) or by in vitro calcium deprivation of the incubation medium.The stimulating effects of CsA on glomerular cyclic GMP content were inhibited by in vivo administration of the ETB receptor antagonist BQ-788 (2 mg kg−1) but not by the ETA receptor antagonist BQ-123 (2 mg kg−1).The maximum increase in glomerular cyclic GMP content induced in vitro by acetylcholine (100 μM) and by ET-3 (100 nM) was slightly lower (approximately by 20–25%, P<0.05) in glomeruli from CsA-treated rats than in glomeruli from untreated rats. In contrast, the maximum increase achieved with 1 μM sodium nitroprusside was similar in both groups.A single subcutaneous injection of CsA did not significantly alter the glomerular mRNA expression of constitutive endothelial NO synthase (eNOS), as evaluated by RT–PCR, whereas the mRNA expression of the inducible NO synthase (iNOS), which follows pretreatment with lipopolysaccharide, was prevented.These results indicate that in vivo administration of a single dose of cyclosporine A transiently increases the cyclic GMP content of freshly isolated glomeruli, and that activation of ETB receptors and stimulation of the NO pathway are involved in this process. Furthermore, a single administration of CsA does not impair eNOS mRNA expression and only slightly reduces NO-dependent glomerular cyclic GMP production.A transient two fold increase in the cyclic GMP content was observed in rat freshly isolated glomeruli 6 to 9 h after a single subcutaneous injection of 20 mg kg−1 cyclosporine A (CsA) in conscious animals.In vitro stimulation with endothelin 3 (ET-3) of isolated glomeruli obtained from CsA-untreated rats resulted in a dose-dependent increase in cyclic GMP content. The increase observed with 10 nM ET-3 was similar to that observed in glomeruli isolated 9 h after in vivo CsA administration.The rise in glomerular cyclic GMP content after in vivo CsA injection was prevented by in vivo treatment with L-NAME (10 mg kg−1) or by in vitro calcium deprivation of the incubation medium.The stimulating effects of CsA on glomerular cyclic GMP content were inhibited by in vivo administration of the ETB receptor antagonist BQ-788 (2 mg kg−1) but not by the ETA receptor antagonist BQ-123 (2 mg kg−1).The maximum increase in glomerular cyclic GMP content induced in vitro by acetylcholine (100 μM) and by ET-3 (100 nM) was slightly lower (approximately by 20–25%, P<0.05) in glomeruli from CsA-treated rats than in glomeruli from untreated rats. In contrast, the maximum increase achieved with 1 μM sodium nitroprusside was similar in both groups.A single subcutaneous injection of CsA did not significantly alter the glomerular mRNA expression of constitutive endothelial NO synthase (eNOS), as evaluated by RT–PCR, whereas the mRNA expression of the inducible NO synthase (iNOS), which follows pretreatment with lipopolysaccharide, was prevented.These results indicate that in vivo administration of a single dose of cyclosporine A transiently increases the cyclic GMP content of freshly isolated glomeruli, and that activation of ETB receptors and stimulation of the NO pathway are involved in this process. Furthermore, a single administration of CsA does not impair eNOS mRNA expression and only slightly reduces NO-dependent glomerular cyclic GMP production.
Canadian Journal of Physiology and Pharmacology, 2002
We investigated the effects of a 3-week treatment with various combinations of angiotensin-conver... more We investigated the effects of a 3-week treatment with various combinations of angiotensin-converting enzyme inhibitor (ACEI) and B 1 and B 2 bradykinin receptor (B 1 R and B 2 R) antagonists (B 1 A and B 2 A) and AT1 receptor antagonist on ERK 1 and 2 phosphorylation in isolated glomeruli from streptozotocin-treated diabetic rats (STZ rats). Body weight, glycemia, and blood pressure were monitored. The rats were divided into nine groups: (1) control; and groups 2-9 were STZ treated with (3) insulin, (4) ACEI, (5) ACEI + B 1 A, (6) ACEI + B 2 A, (7) B 2 A, (8) B 1 A, (9) AT1 antagonist. ERK 1 and 2 phosphorylation and expression of B 1 R and B 2 R were assessed by Western blot analysis. ERK 1 and 2 phosphorylation was higher in STZ rats; this activation was normalized by insulin and reduced by ACEI but not by AT1 antagonist. The reduction of ERK 1 and 2 phosphorylation by the ACEI was reversed by B 1 A and B 2 A. The induction of B 1 R was confirmed by increased expression of mRNA and B 1 receptor protein. Since ERK 1 and 2 phosphorylation is an early event in the induction of matrix secretion and hyperproliferation associated with diabetic nephropathy, activation of B 1 R and B 2 R appears to be a useful pharmacological target in the management of this pathology.
Anesthesiology, 2008
The aim of this study was to validate a model of postfracture pain in mice, which was evaluated i... more The aim of this study was to validate a model of postfracture pain in mice, which was evaluated in the presence and the absence of morphine and ketoprofen. The study was divided into two parts: protocol A, the effects of closed fracture; and protocol B, the effects of morphine and ketoprofen on fracture pain. In protocol A, mice were assigned to three groups: group 1, sham incision; group 2, sham pinning; or group 3, fracture. In protocol B, mice were randomly assigned to four groups to receive morphine (3 or 10 mg/kg body weight), ketoprofen (50 mg/kg body weight), or placebo (vehicle). Three tests were used to assess pain behavior: von Frey filament application, hot plate test, and a subjective pain scale. In protocol A, thermal nociception, mechanical nociception, and subjective pain were significantly modified in group 3 (fractured) compared with control groups 1 and 2 (sham groups). In protocol B, when tests were repeated for 240 min in morphine-treated animals and in ketoprofen-treated animals, reduction of mechanical nociception, thermal nociception, and subjective pain scale score were observed. Morphine and ketoprofen administration provided the same effect on behavioral testing on postoperative days 1 and 2. This mouse model seems to be a reliable and reproducible tool to investigate the effect of closed bone fracture on several parameters, such as pain, remodeling, and recovery. Moreover, it allows studying the effects of various pharmacologic treatments as well as the involvement of various systems using different genetically modified strains of mice.
Kidney International, 2002
leading to diabetic nephropathy. Insulin-like growth facgenesis in mesangial cells by bradykinin.... more leading to diabetic nephropathy. Insulin-like growth facgenesis in mesangial cells by bradykinin. tor-I (IGF-I) and to a lesser extent insulin, both induce Background. The beneficial effects of therapeutic angioten-MC proliferation and collagen secretion most likely via sin-converting enzyme (ACE) inhibitor treatment against the
European Journal of Pharmacology, 1995
This study examined the effect of various manipulations of intracellular Ca2+ on kallikrein relea... more This study examined the effect of various manipulations of intracellular Ca2+ on kallikrein release by renal cortical slices. Increasing the extracellular Ca2+ concentration and the addition of Ca2+ ionophore A23187 was without effect on kallikrein release. In contrast, kallikrein release was enhanced by the addition of either extracellular or intracellular Ca2+ chelators in Ca(2+)-free medium and by two Ca2+ channel blockers, verapamil and nifedipine. Kallikrein release was also highly enhanced in depolarising medium (10-100 mM potassium chloride). Since potassium chloride induced a dose-related increase in free cytosolic Ca2+ which was abolished by nifedipine whereas the stimulation of kallikrein secretion persisted, a direct stimulating effect of potassium, at least at sub-physiological concentration, is suggested. Similarily, inhibition of either sodium/potassium-ATPase and Ca2+ ATPase by ouabain and vanadium respectively, was also without effect on kallikrein secretion. Taken together, these results indicate that intracellular Ca2+ depletion, Ca2+ channel blockers and high extracellular K+ concentrations, acting through different mechanisms, are effective stimuli for kallikrein secretion, at least in the isolated renal cortical slice.
Kidney International, 1998
Background. Under physiological conditions, the effects of kinins in the kidney are mainly mediat... more Background. Under physiological conditions, the effects of kinins in the kidney are mainly mediated by the bradykinin B2-receptor, whereas the kinin B1-receptor is strongly induced under inflammatory conditions in a variety of tissues. Knowledge of the distribution of the B1-receptor along the nephron is of importance since the B1-receptor might replace B2-receptors under these conditions.
European Journal of Pharmacology, 1995
We investigated the effects of bradykinin on glomerular bradykinin B2 receptor functions and para... more We investigated the effects of bradykinin on glomerular bradykinin B2 receptor functions and parameters in vivo, after intrarenal infusion of bradykinin, and in vitro, after incubation of isolated rat glomeruli with bradykinin. Bradykinin transiently increased renal plasma flow whereas a second challenge was ineffective. Scatchard analysis demonstrated the presence of two populations of bradykinin binding sites whose densities were similarly decreased by about 40% after intrarenal bradykinin infusion. This decrease was not altered by an acid wash suggesting internalization of the radiolabelled ligand. The effect of bradykinin was prevented by a bradykinin B2 receptor antagonist. Pre-exposure of isolated rat glomeruli to bradykinin mimicked the in vivo results because there was a reduction in bradykinin-induced prostaglandin E2 and prostaglandin F2 alpha release. Rapid recovery was observed 15 min after washing out the bradykinin. Our results directly demonstrate a negative homologous down-regulation of B2 glomerular bradykinin receptor density under both in vivo and in vitro conditions, an effect which involves a rapid sequestration of the receptor.
Background-The physiological effects of ACE inhibitors may act in part through a kinin-dependent ... more Background-The physiological effects of ACE inhibitors may act in part through a kinin-dependent mechanism. We investigated the effect of chronic ACE-inhibitor treatment on functional kinin B 1 -and B 2 -receptor expression, which are the molecular entities responsible for the biological effects of kinins. Methods and Results-Rats were subjected to different 6-week treatments using various mixtures of the following agents: ACE inhibitor, angiotensin AT 1 -receptor antagonist, and B 1 -and B 2 -receptor antagonists. Chronic ACE inhibition induced both renal and vascular B 1 -receptor expression, whereas B 2 -receptor expression was not modified. Furthermore, with B 1 -receptor antagonists, it was shown that B 1 -receptor induction was involved in the hypotensive effect of ACE inhibition. Using microdissection, we prepared 10 different nephron segments and found ACE-inhibitor-induced expression of functional B 1 -receptors in all segments. ACE-inhibitor-induced B 1 -receptor induction involved homologous upregulation, because it was prevented by B 1 -receptor antagonist treatment. Finally, using B 2 -receptor knockout mice, we showed that ACE-inhibitor-induced B 1 -receptor expression was B 2 -receptor independent. Conclusions-This study provides the first evidence that chronic ACE-inhibitor administration is associated with functional vascular and renal B 1 -receptor induction, which is involved in ACE-inhibitor-induced hypotension. The observed B 1 -receptor induction in the kidney might participate in the known renoprotective effects of ACE inhibition.
In addition to being a pro-inflammatory mediator, bradykinin is now recognized as a neuromediator... more In addition to being a pro-inflammatory mediator, bradykinin is now recognized as a neuromediator and regulator of several vascular and renal functions. New breakthroughs point to unusual and atypical signalling pathways for a G-protein coupled receptor that could explain the anti-proliferative and anti-fibrogenic effects of bradykinin. The availability of transgenic and knock out animal models for bradykinin receptors or bradykinin-synthesizing or -catabolic enzymes confirms these cardiac and renal protective roles for this peptide system. Bradykinin receptors are involved in the therapeutic action of angiotensin-1 converting enzyme inhibitors that are used in the treatment of arterial hypertension, heart failure and diabetes. Nevertheless, recent evidence highlights dissimilar mechanisms in the regulation and function of these receptors between the central nervous system and peripheral tissues. Therefore, the development of more specific bradykinin receptor agonists or antagonists devoid of central actions seems to evolve as a new therapeutic approach.
Angiotensin II regulates vascular structure through growth and apoptosis, with implications in pa... more Angiotensin II regulates vascular structure through growth and apoptosis, with implications in pathophysiology. Subtypes of vascular smooth muscle cells with specific morphology, growth, or apoptotic features have been isolated. Here, we investigated the effects of angiotensin II on apoptosis of 2 morphologically different rat aortic smooth muscle cell phenotypes. Spindle and epithelioid cell lines cultured under low serum conditions were stimulated by angiotensin II. Responsiveness was evaluated by calcium signaling. In both phenotypes, an angiotensin II type 1 receptor-mediated transient intracellular calcium peak arose from intracellular pools. However, a sustained nifedipine-sensitive calcium entry occurred specifically in epithelioid cells. Angiotensin II did not impair spindle cell survival, whereas a delayed reduction in cell number occurred in epithelioid cells. Cell death through apoptosis was characterized by cellular and nuclear morphology. Consistently, DNA fragmentation, evaluated by biochemical quantification, nuclei staining, and ladders, and caspase 3-like activity were promoted by angiotensin II in epithelioid cells. Kinetics of annexin V binding showed that apoptosis was a delayed process. Angiotensin II-induced apoptosis of epithelioid cells was prevented by angiotensin II type 1 but not type 2 receptor antagonists and was inhibited by a calcium chelator or calcium antagonist. Conversely, epithelioid cell apoptosis could be induced by a calcium ionophore. Thus, the death signaling promoted by angiotensin II in epithelioid cells involves type 1 receptor-mediated calcium entry. These data suggest that angiotensin II can promote angiotensin II type 1 receptor-mediated apoptosis in vascular smooth muscle cells, depending on their phenotype. This process may play a role in vascular remodeling in cardiovascular diseases. (Hypertension. 2001;38: 1294-1299.)
Canadian Journal of Physiology and Pharmacology, 2002
Several experimental data document an activation of the mitogen-activated protein kinases Erk1 an... more Several experimental data document an activation of the mitogen-activated protein kinases Erk1 and Erk2 by bradykinin (BK), an agonist of the kinin B2 receptor (B2R). In contrast, other reports showed an inhibitory modulation of mitogenesis by BK. Therefore, we explored in the isolated glomeruli the effect of B2R activation on the signaling of insulin-like growth factor-1 (IGF-1), platelet-derived growth factor-BB (PDGF-BB), and high glucose (HG), three factors that are believed to be involved in the development of glomerulosclerosis via the phosphorylation of Erk1 and Erk2. We observed that the activation of B2R negatively modulates the phosphorylation of Erk1 and Erk2 induced by IGF-1, PDGF-BB, and HG in the glomerulus. These effects are consistent with the hypothesis of a protective role for BK in the kidney during development of glomerulosclerosis and renal pathologies associated with a hyperproliferative state.
Bradykinin B2 receptor knockout mice (B 2 -/-) have been useful to study the role of bradykinin u... more Bradykinin B2 receptor knockout mice (B 2 -/-) have been useful to study the role of bradykinin under pathological conditions. Using these mice it was shown that bradykinin plays an important role in angiogenesis, heart failure, salt induced hypertension and kidney fibrosis.